U.S. patent application number 11/552624 was filed with the patent office on 2007-07-05 for cucurbituril-containing gel and method of preparing the same.
This patent application is currently assigned to POSTECH FOUNDATION. Invention is credited to Il Ha HWANG, Woo Sung JEON, Dongwoo KIM, Hee Joon KIM, Kimoon KIM, Erumaipatty R. NAGARAJAN, Narayanan SELVAPALAM.
Application Number | 20070154553 11/552624 |
Document ID | / |
Family ID | 38224735 |
Filed Date | 2007-07-05 |
United States Patent
Application |
20070154553 |
Kind Code |
A1 |
KIM; Kimoon ; et
al. |
July 5, 2007 |
CUCURBITURIL-CONTAINING GEL AND METHOD OF PREPARING THE SAME
Abstract
Provided are a gel including a compound represented by Formula 1
below and a method of preparing the same: ##STR00001## wherein n,
X, A.sub.1, and A.sub.2 are as defined in the specification.
Inventors: |
KIM; Kimoon; (Pohang-city,
KR) ; HWANG; Il Ha; (Pohang-city, KR) ; JEON;
Woo Sung; (Pohang-city, KR) ; KIM; Hee Joon;
(Pohang-city, KR) ; KIM; Dongwoo; (Pohang-city,
KR) ; SELVAPALAM; Narayanan; (Pohang-city, KR)
; NAGARAJAN; Erumaipatty R.; (Pohang-city, KR) |
Correspondence
Address: |
ROTHWELL, FIGG, ERNST & MANBECK, P.C.
1425 K STREET, N.W., SUITE 800
WASHINGTON
DC
20005
US
|
Assignee: |
POSTECH FOUNDATION
Pohang-city
KR
POSTECH ACADEMY-INDUSTRY FOUNDATION
Pohang-city
KR
|
Family ID: |
38224735 |
Appl. No.: |
11/552624 |
Filed: |
October 25, 2006 |
Current U.S.
Class: |
424/484 ;
424/133.1; 424/85.1; 424/85.4; 424/94.4; 424/94.63; 514/10.8;
514/10.9; 514/11.1; 514/11.5; 514/11.7; 514/171; 514/18.5; 514/393;
514/5.9; 514/7.7; 514/8.1; 514/8.4; 514/8.5 |
Current CPC
Class: |
A61K 9/06 20130101; A61K
41/0042 20130101; A61K 47/16 20130101; A61K 38/00 20130101; A61K
31/573 20130101 |
Class at
Publication: |
424/484 ;
424/85.1; 424/133.1; 424/94.63; 514/12; 514/3; 514/9; 424/85.4;
424/94.4; 514/171; 514/393 |
International
Class: |
A61K 38/28 20060101
A61K038/28; A61K 38/31 20060101 A61K038/31; A61K 38/27 20060101
A61K038/27; A61K 38/25 20060101 A61K038/25; A61K 38/26 20060101
A61K038/26; A61K 38/24 20060101 A61K038/24; A61K 38/22 20060101
A61K038/22; A61K 38/21 20060101 A61K038/21; A61K 38/19 20060101
A61K038/19; A61K 31/573 20060101 A61K031/573; A61K 9/14 20060101
A61K009/14 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 4, 2006 |
KR |
10-2006-0000892 |
Claims
1. A gel comprising a compound represented by Formula 1 below:
##STR00006## wherein n is an integer of 4 to 20; X is O, S, or NH;
and A.sub.1 and A.sub.2 are each independently H, OR, SR, or NHR
where R is selected from the group consisting of H, substituted or
unsubstituted C.sub.1-C.sub.30 alkyl, substituted or unsubstituted
C.sub.2-C.sub.30 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.30 alkynyl, substituted or unsubstituted
C.sub.2-C.sub.30 carbonylalkyl, substituted or unsubstituted
C.sub.1-C.sub.30 thioalkyl, substituted or unsubstituted
C.sub.1-C.sub.30 alkylthiol, substituted or unsubstituted
C.sub.1-C.sub.30 hydroxyalkyl, substituted or unsubstituted
C.sub.1-C.sub.30 alkylsilyl, substituted or unsubstituted
C.sub.1-C.sub.30 aminoalkyl, substituted or unsubstituted
C.sub.1-C.sub.30 aminoalkylthioalkyl, substituted or unsubstituted
C.sub.5-C.sub.30 cycloalkyl, substituted or unsubstituted
C.sub.2-C.sub.30 heterocycloalkyl, substituted or unsubstituted
C.sub.6-C.sub.30 aryl, substituted or unsubstituted
C.sub.6-C.sub.20 arylalkyl, substituted or unsubstituted
C.sub.4-C.sub.30 heteroaryl, and substituted or unsubstituted
C.sub.4-C.sub.30 heteroarylalkyl.
2. The gel of claim 1, wherein A1 or A2 is an allyloxy group.
3. The gel of claim 1, wherein n is 7, X is O, and A1 and A2 are
each H.
4. The gel of claim 1, wherein the content of the compound of
Formula 1 is 1 to 10 wt %.
5. The gel of claim 1, further comprising an acid.
6. The gel of claim 5, wherein the acid is selected from the group
consisting of sulfuric acid, hydrochloric acid, nitric acid,
phosphoric acid, chloric acid, HBF4, HPF6, acetic acid,
trifluoroacetic acid, oxalic acid, benzoic acid, ascorbic acid, and
HAuCl4.
7. The gel of claim 1, further comprising a base.
8. The gel of claim 7, wherein the base is selected from the group
consisting of sodium hydroxide, potassium hydroxide, calcium
hydroxide, methylamine, ethylamine, pyridine, and aniline.
9. The gel of claim 1, further comprising a pharmacologically
active substance.
10. The gel of claim 9, wherein the pharmacologically active
substance is an organic compound selected from the group consisting
of hydrocortisone, prednisolone, spironolatone, testosterone,
megestrol acetate, danasol, progesterone, indometasine,
amphotericin B, and a combination thereof.
11. The gel of claim 9, wherein the pharmacologically active
substance is a protein selected from the group consisting of human
growth hormone, G-CSF (granulocyte colony-stimulating factor),
GM-CSF (granulocyte-macrophage colony-stimulating factor),
erythropoietin, vaccine, antibody, insulin, glucagon, calcitonin,
ACTH (adrenocorticotropic hormone), somatostatin, somatotropin,
somatomedin, parathormone, thyroxine, a substance secreted from
hypothalamus, prolactin, endorphin, VEGF (vascular endothelial
growth factor), enkephalin, vasopressin, nerve growth factor,
non-naturally occurring opioid, interferon, asparaginase, alginase,
superoxide dismutase, trypsin, chymotrypsin, pepsin, and a
combination thereof.
12. The gel of claim 1, further comprising a stimulus-responsive
compound.
13. The gel of claim 12, wherein the stimulus-responsive compound
is a light-responsive compound.
14. The gel of claim 13, wherein the stimulus-responsive compound
comprises an azobenzene group or a stilbene group.
15. The gel of claim 12, wherein the stimulus-responsive compound
is a compound undergoing a change in structure or oxidation state
in response to an electrochemical stimulus.
16. The gel of claim 15, wherein the stimulus-responsive compound
is quinone, benzoquinone, naphthoquinone, anthraquinone,
hydroquinone, catechol, viologen, or a compound comprising one of
these.
17. The gel of claim 12, wherein the stimulus-responsive compound
is a pH-responsive compound.
18. A method of preparing a gel, the method comprising: (i)
dissolving a compound represented by Formula 1 below in a solvent
to prepare a sol; (ii) adding a pharmacologically active substance
to the sol of (i); and (iii) converting the resultant
pharmacologically active substance-containing sol of (ii) to a gel:
##STR00007## wherein n, X, A.sub.1, and A.sub.2 are as defined in
claim 1.
19. A method of preparing a gel, the method comprising: (i) mixing
a compound represented by Formula 1 below with a pharmacologically
active substance; (ii) adding a solvent to the resultant mixture of
(i) to prepare a sol; and (iii) converting the sol of (ii) to a
gel: ##STR00008## wherein n, X, A.sub.1, and A.sub.2 are as defined
in claim 1.
20. A method of preparing a gel, the method comprising: (i)
dissolving a compound represented by Formula 1 below in a solvent
to prepare a sol; (ii) adding a stimulus-responsive compound to the
sol of (i); and (iii) converting the resultant stimulus-responsive
compound-containing sol of (ii) to a gel: ##STR00009## wherein n,
X, A.sub.1, and A.sub.2 are as defined in claim 1.
21. The method of claim 20, wherein in (i) or (ii), a
pharmacologically active substance is further added.
22. A method of preparing a gel, the method comprising: (i) mixing
a compound represented by Formula 1 below with a
stimulus-responsive compound; (ii) adding a solvent to the
resultant mixture of (i) to prepare a sol; and (iii) converting the
sol of (ii) to a gel: ##STR00010## wherein n, X, A.sub.1, and
A.sub.2 are as defined in claim 1.
23. The method of claim 22, wherein in (i) or (ii), a
pharmacologically active substance is further added.
Description
CROSS-REFERENCE TO RELATED PATENT APPLICATION
[0001] This application claims priority from Korean Patent
Application No. 10-2006-0000892, filed on Jan. 4, 2006, in the
Korean Intellectual Property Office, the disclosure of which is
incorporated herein in its entirety by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a gel and a preparation
method thereof, and more particularly, to a cucurbituril-containing
gel and a method of preparing the same.
DESCRIPTION OF THE RELATED ART
[0003] A gel, which is an intermediate state between solid and
liquid, is a jellylike material that solvent molecules are trapped
inside the network of aggregates of a gel-forming agent called
"gelator". A colloidal suspension that gelator molecules are
dissolved in a solvent is called "sol".
[0004] Generally, a gel is prepared as follows. Gelator molecules
are mixed with a solvent and the resultant mixture is heated so
that the gelator molecules are completely dissolved in the solvent
to obtain a sol. Then, the sol is gradually cooled to a room
temperature whereupon it transforms into a gel. The heating process
may be omitted according to the type of the gelator molecules.
[0005] A gel phase is obtained by an intermolecular interaction
between a solvent and a gelator. A gel is classified into a polymer
gel and a low-molecular-weight gel according to the molecular
weight of a gelator and into an organogel and a hydrogel according
to the type of a solvent.
[0006] Gel formation (gelation) occurs by a weak interaction, such
as a hydrophobic interaction or a hydrogen bond, between a gelator
and a solvent, and a gel is maintained in a jellylike state by an
appropriate weak-interaction between a gelator and a solvent.
[0007] Generally, gelator molecules are self-assembled to form
elongated fibrous structures with nanometer to micrometer
thickness, and a gel is a mesh-like aggregate of the fibrous
structures. At this time, the fibrous structures encompass a large
number of solvent molecules. Due to such structural
characteristics, a gel has a larger number of voids than other
materials. Gel voids can also be filled with various materials, in
addition to solvent molecules, while maintaining the structure of a
gel.
[0008] Cucurbituril was first reported by R. Behrend, E. Meyer, and
F. Rusche in 1905. In 1981, W. Mock and coworkers characterized the
cucurbituril as a hexameric macrocyclic compound with the
composition of C36H36N24O12, and elucidated the crystal structure
of the cucurbituril by X-ray diffraction [J. Am. Chem. Soc. 1981,
103, 7367]. They named it cucurbit[6]uril. In early 2000, Kimoon
Kim and coworkers reported the improved preparation and separation
of well-known cucurbit[6]uril and its homologues, cucurbit[n]urils
(n=5, 7, 8), and identified their X-ray crystal structures [J. Am.
Chem. Soc. 2000, 122, 540].
[0009] Meanwhile, PCT International Publication WO 00/68232
discloses cucurbit[n]uril represented by Reference Diagram 1
below:
##STR00002##
[0010] wherein n is an integer of 4 to 12.
[0011] The above-described cucurbiturils are compounds consisting
of unsubstituted glycoluril monomer units.
[0012] Cucurbiturils are macrocyclic compounds and have a
lipophilic cavity and two hydrophilic entrances at upper and lower
portions. Thus, lipophilic interactions occur in the cavity of
cucurbiturils, and hydrogen bonds, polar-polar interactions, and
positive charge-polar interactions occur in the two entrances
having six carbonyl groups. Therefore, cucurbiturils have retention
capacity for various compounds by a very stable non-covalent
linkage with these compounds. Cucurbiturils form a very stable
non-covalent linkage, in particular, with compounds having a
functional group such as an amino group or a carboxyl group. Based
on such characteristics, studies about development of drug delivery
systems using cucurbiturils have been continuously conducted.
[0013] Recently, the present inventors reported a stable
non-covalent complex formation between oxaliplatin approved as an
anticancer agent by the Food Drug Administration (FDA) and
cucurbituril used as a drug delivery system (WO03/024978).
SUMMARY OF THE INVENTION
[0014] The present invention provides a gel including a
cucurbituril homologue or derivative.
[0015] The present invention also provides a method of preparing
the gel.
[0016] According to an aspect of the present invention, there is
provided a gel including a compound represented by Formula 1
below:
##STR00003##
[0017] wherein n is an integer of 4 to 20;
[0018] X is O, S, or NH; and
[0019] A.sub.1 and A.sub.2 are each independently H, OR, SR, or NHR
where R is selected from the group consisting of H, substituted or
unsubstituted C.sub.1-C.sub.30 alkyl, substituted or unsubstituted
C.sub.2-C.sub.30 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.30 alkynyl, substituted or unsubstituted
C.sub.2-C.sub.30 carbonylalkyl, substituted or unsubstituted
C.sub.1-C.sub.30 thioalkyl, substituted or unsubstituted
C.sub.1-C.sub.30 alkylthiol, substituted or unsubstituted
C.sub.1-C.sub.30 hydroxyalkyl, substituted or unsubstituted
C.sub.1-C.sub.30 alkylsilyl, substituted or unsubstituted
C.sub.1-C.sub.30 aminoalkyl, substituted or unsubstituted
C.sub.1-C.sub.30 aminoalkylthioalkyl, substituted or unsubstituted
C.sub.5-C.sub.30 cycloalkyl, substituted or unsubstituted
C.sub.2-C.sub.30 heterocycloalkyl, substituted or unsubstituted
C.sub.6-C.sub.30 aryl, substituted or unsubstituted
C.sub.6-C.sub.20 arylalkyl, substituted or unsubstituted
C.sub.4-C.sub.30 heteroaryl, and substituted or unsubstituted
C.sub.4-C.sub.30 heteroarylalkyl.
[0020] According to another aspect of the present invention, there
is provided a method of preparing a gel, the method including: (i)
dissolving the compound of Formula 1 above in a solvent to prepare
a sol; (ii) adding a pharmacologically active substance to the sol
of (i); and (iii) converting the resultant pharmacologically active
substance-containing sol of (ii) to a gel.
[0021] According to still another aspect of the present invention,
there is provided a method of preparing a gel, the method
including: (i) mixing the compound of Formula 1 above with a
pharmacologically active substance; (ii) adding a solvent to the
resultant mixture of (i) to prepare a sol; and (iii) converting the
sol of (ii) to a gel.
[0022] According to yet another aspect of the present invention,
there is provided a method of preparing a gel, the method
including: (i) dissolving the compound of Formula 1 above in a
solvent to prepare a sol; (ii) adding a stimulus-responsive
compound to the sol of (i); and (iii) converting the resultant
stimulus-responsive compound-containing sol of (ii) to a gel.
[0023] According to a further aspect of the present invention,
there is provided a method of preparing a gel, the method
including: (i) mixing the compound of Formula 1 above with a
stimulus-responsive compound; (ii) adding a solvent to the
resultant mixture of (i) to prepare a sol; and (iii) converting the
sol of (ii) to a gel.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] The above and other features and advantages of the present
invention will become more apparent by describing in detail
exemplary embodiments thereof with reference to the attached
drawings in which:
[0025] FIG. 1 is an Atomic Force Microscopic (AFM) image of the gel
phase of a composition prepared by dissolving cucurbit[7]uril in an
aqueous sulfuric acid solution and a schematic diagram illustrating
a gel-forming process;
[0026] FIG. 2 is images of the sol and gel phases of a composition
prepared by dissolving cucurbit[7]uril in distilled water;
[0027] FIG. 3 is an AFM image of the gel phase of a composition
prepared by dissolving cucurbit[7]uril in distilled water;
[0028] FIG. 4 is an AFM image of the gel phase of a composition
prepared by dissolving cucurbit[7]uril in distilled water followed
by addition of a concentrated sulfuric acid;
[0029] FIG. 5 is a graph illustrating an absorbance with respect to
a temperature for a composition prepared by dissolving
cucurbit[7]uril in a sulfuric acid solution;
[0030] FIG. 6 is an image of the gel phase of a composition
prepared by dissolving cucurbit[7]uril in a sulfuric acid solution
followed by addition of oxaliplatin;
[0031] FIG. 7 is images of the sol and gel phases of a composition
prepared by dissolving cucurbit[7]uril in a sulfuric acid solution
followed by addition of trans-diaminostilbene;
[0032] FIG. 8 is a cyclic voltammogram showing a sol-gel phase
transition in response to a electrochemical stimulus for a
composition prepared by dissolving cucurbit[7]uril in a sulfuric
acid solution followed by addition of benzoquinone; and
[0033] FIG. 9 is images of the sol and gel phases of a composition
prepared by dissolving cucurbit[7]uril in a sulfuric acid solution
followed by addition of benzoquinone.
DETAILED DESCRIPTION OF THE INVENTION
[0034] The present invention will now be described more fully with
reference to the accompanying drawings, in which exemplary
embodiments of the invention are shown.
[0035] The present invention provides a gel including a compound
represented by Formula 1 below, i.e., a cucurbituril homologue or
derivative:
##STR00004##
[0036] wherein n is an integer of 4 to 20;
[0037] X is O, S, or NH; and
[0038] A.sub.1 and A.sub.2 are each independently H, OR, SR, or NHR
where R is selected from the group consisting of H, substituted or
unsubstituted C.sub.1-C.sub.30 alkyl, substituted or unsubstituted
C.sub.2-C.sub.30 alkenyl, substituted or unsubstituted
C.sub.2-C.sub.30 alkynyl, substituted or unsubstituted
C.sub.2-C.sub.30 carbonylalkyl, substituted or unsubstituted
C.sub.1-C.sub.30 thioalkyl, substituted or unsubstituted
C.sub.1-C.sub.30 alkylthiol, substituted or unsubstituted
C.sub.1-C.sub.30 hydroxyalkyl, substituted or unsubstituted
C.sub.1-C.sub.30 alkylsilyl, substituted or unsubstituted
C.sub.1-C.sub.30 aminoalkyl, substituted or unsubstituted
C.sub.1-C.sub.30 aminoalkylthioalkyl, substituted or unsubstituted
C.sub.5-C.sub.30 cycloalkyl, substituted or unsubstituted
C.sub.2-C.sub.30 heterocycloalkyl, substituted or unsubstituted
C.sub.6-C.sub.30 aryl, substituted or unsubstituted
C.sub.6-C.sub.20 arylalkyl, substituted or unsubstituted
C.sub.4-C.sub.30 heteroaryl, and substituted or unsubstituted
C.sub.4-C.sub.30 heteroarylalkyl.
[0039] The gel according to the present invention can be prepared
by dissolving the compound of Formula 1 above used as a gelator in
an appropriate solvent.
[0040] In the compound of Formula 1 above, A1 or A2 may be an
allyloxy group.
[0041] In the compound of Formula 1 above, n may be 7, X may be O,
and A1 and A2 may be each H.
[0042] The gel of the present invention may include 1-10 wt % of
the compound of Formula 1 above.
[0043] A solvent that can be used in preparation of the gel of the
present invention may be distilled water, an acidic solution, a
basic solution, etc.
[0044] In the present invention, gelation using the compound of
Formula 1 above is more efficiently promoted in the presence of an
acid or a base than in the absence of an acid or a base. For
example, in the absence of an acid or a base, gelation occurs about
one day after a cucurbituril used as a gelator is dissolved in a
solvent. On the other hand, in the presence of an appropriate acid
or base, gelation occurs immediately or in a short time after a
cucurbituril used as a gelator is dissolved in a solvent.
[0045] Examples of an acid that can be used herein include an
inorganic acid such as sulfuric acid, hydrochloric acid, nitric
acid, phosphoric acid, chloric acid, HBF4, or HPF6; an organic acid
such as acetic acid, trifluoroacetic acid, oxalic acid, benzoic
acid, or ascorbic acid; and a metal-containing acid such as
HAuCl4.
[0046] Examples of a base that can be used herein include an
inorganic base such as sodium hydroxide, potassium hydroxide, or
calcium hydroxide; and an organic base such as ammonia,
methylamine, ethylamine, pyridine, or aniline.
[0047] The gel according to the present invention may further
include a pharmacologically active substance. A pharmacologically
active substance-containing gel can be prepared by (i)
non-covalently attaching a pharmacologically active substance into
a cavity of a cucurbituril homologue or derivative molecule and
dissolving the resultant non-covalent complex in a solvent or (ii)
dissolving a pharmacologically active substance in a solvent and
dissolving a cucurbituril homologue or derivative in the resultant
solution.
[0048] A pharmacologically active substance that can be used herein
is not particularly limited provided that it has pharmacological
activity and can be dissolved or dispersed in a solvent used in gel
preparation. For example, the pharmacologically active substance
may be an organic compound, a protein, a gene, etc.
[0049] Examples of the organic compound include, but are not
limited to, hydrocortisone, prednisolone, spironolatone,
testosterone, megestrol acetate, danasol, progesterone,
indometasine, amphotericin B, and a combination thereof.
[0050] Examples of the protein include, but are not limited to,
human growth hormone, G-CSF (granulocyte colony-stimulating
factor), GM-CSF (granulocyte-macrophage colony-stimulating factor),
erythropoietin, vaccine, antibody, insulin, glucagon, calcitonin,
ACTH (adrenocorticotropic hormone), somatostatin, somatotropin,
somatomedin, parathormone, thyroxine, a substance secreted from
hypothalamus, prolactin, endorphin, VEGF (vascular endothelial
growth factor), enkephalin, vasopressin, nerve growth factor,
non-naturally occurring opioid, interferon, asparaginase, alginase,
superoxide dismutase, trypsin, chymotrypsin, pepsin, and a
combination thereof.
[0051] The gel according to the present invention may further
include a stimulus-responsive compound. As used herein, the term
"stimulus-responsive compound" refers to a compound that controls
the formation and break-up of a gel in response to an external
stimulus, such as light, an electrochemical stimulus, or pH change.
For example, the stimulus-responsive compound may include a portion
undergoing a change in structure or oxidation state under an
applied electrochemical voltage, a temperature change, or a pH
change.
[0052] A light-responsive compound may be a compound including an
azobenzene group or a stilbene group, and an electrochemical
stimulus-responsive compound may be quinone, benzoquinone,
naphthoquinone, anthraquinone, hydroquinone, catechol, viologen, or
a compound including one of these. A stimulus-responsive
compound-containing gel is referred to as "stimulus-responsive
gel".
[0053] A stimulus-responsive gel can be prepared by (i)
non-covalently attaching a stimulus-responsive compound into the
cavity of a cucurbituril homologue or derivative molecule and
dissolving the resultant non-covalent complex in a solvent or (ii)
dissolving a stimulus-responsive compound in a solvent and
dissolving a cucurbituril homologue or derivative in the resultant
solution.
[0054] The gel according to the present invention may also include
both a stimulus-responsive compound and a pharmacologically active
substance. In this case, the gel is used as a stimulus-responsive
drug-release gel capable of releasing a pharmacologically active
substance in response to an external stimulus, such as light,
temperature change, or pH change.
[0055] The present invention also provides a method of preparing a
gel including a cucurbituril homologue or derivative of Formula 1
below:
##STR00005##
[0056] wherein n, X, A.sub.1, and A.sub.2 are as defined above.
[0057] More specifically, the present invention provides a method
of preparing a gel, the method including: (i) dissolving the
compound of Formula 1 above in a solvent to prepare a sol; (ii)
adding a pharmacologically active substance to the sol of (i); and
(iii) converting the resultant pharmacologically active
substance-containing sol of (ii) to a gel. In this case, in (i) or
(ii), a stimulus-responsive compound may further be added.
[0058] The present invention also provides a method of preparing a
gel, the method including: (i) mixing the compound of Formula 1
above with a pharmacologically active substance; (ii) adding a
solvent to the resultant mixture of (i) to prepare a sol; and (iii)
converting the sol of (ii) to a gel. In this case, in (i) or (ii),
a stimulus-responsive compound may further be added.
[0059] The present invention also provides a method of preparing a
gel, the method including: (i) dissolving the compound of Formula 1
above in a solvent to prepare a sol; (ii) adding a
stimulus-responsive compound to the sol of (i); and (iii)
converting the resultant stimulus-responsive compound-containing
sol of (ii) to a gel. In this case, in (i) or (ii), a
pharmacologically active substance may further be added.
[0060] The present invention also provides a method of preparing a
gel, the method including: (i) mixing the compound of Formula 1
above with a stimulus-responsive compound; (ii) adding a solvent to
the resultant mixture of (i) to prepare a sol; and (iii) converting
the sol of (ii) to a gel. In this case, in (i) or (ii), a
pharmacologically active substance may further be added.
[0061] The solvent used in the gel preparation method of the
present invention may be distilled water, an acidic solution, or a
basic solution, preferable examples of which are as illustrated
above.
[0062] The addition order of the compound of Formula 1 above, the
pharmacologically active substance, and/or the stimulus-responsive
compound is not an important factor in the gel preparation method
of the present invention.
[0063] The structure of a gel prepared according to the
above-described method can be determined by Atomic Force Microscopy
(AFM) or Scanning Electron Microscopy (SEM). That is, a droplet of
a sol obtained by heating a gel is dropped on a plate and cooled to
a room temperature, and the structure of the resultant gel is
determined by AFM or SEM.
[0064] Hereinafter, the present invention will be described more
specifically with reference to the following working examples.
EXAMPLE 1
Preparation of Cucurbituril-Containing Gels
[0065] (1) 0.1 mL of distilled water was added to 10 mg of
cucurbit[7]uril and the resultant mixture was heated so that the
cucurbit[7]uril was completely dissolved in the distilled water.
The resultant sol-phase composition was cooled to a room
temperature and incubated for one day to produce a gel. The gel
exhibited a thermally reversible gel-sol phase transition in such a
manner that gel-to-sol transition occurred by heating and
sol-to-gel transition occurred by cooling to a room
temperature.
[0066] FIG. 2 is images of the sol ({circle around (1)}) and gel
({circle around (2)}) phases of the composition prepared by
dissolving cucurbit[7]uril in distilled water, and FIG. 3 is an AFM
image of the gel phase of the composition prepared by dissolving
cucurbit[7]uril in distilled water.
[0067] (2) 0.2 mL of distilled water was added to 10 mg of
cucurbit[7]uril and the resultant mixture was heated so that the
cucurbit[7]uril was completely dissolved in the distilled water to
produce a sol-phase composition. Then, 0.01 mL of a concentrated
sulfuric acid (18 M) was added to the sol-phase composition, and
the resultant mixture was incubated to reach a room temperature. As
a result, a gel was produced within 10 minutes after the
incubation. The gel exhibited a thermally reversible gel-sol phase
transition in such a manner that gel-to-sol transition occurred by
heating and sol-to-gel transition occurred by cooling to a room
temperature.
[0068] A droplet of a sol obtained by heating the gel was dropped
on a plate and cooled, and the structure of the resultant gel was
observed using an AFM. The AFM image is shown in FIG. 4. Referring
to FIG. 4, the gel was in the form of an aggregate of fibrils with
micrometer thickness.
[0069] (3) 0.2 mL of a 1 M sulfuric acid solution was added to 10
mg of cucurbit[7]uril and the resultant mixture was heated so that
the cucurbit[7]uril completely dissolved in the sulfuric acid
solution. The resultant sol-phase composition was incubated to
reach a room temperature. As a result, a gel was produced within 10
minutes after the incubation.
[0070] (4) 0.2 mL of a 1 M sodium hydroxide solution was added to
10 mg of cucurbit[7]uril and the resultant mixture was heated so
that the cucurbit[7]uril was completely dissolved in the sodium
hydroxide solution. The sol-phase composition was incubated to
reach a room temperature. As a result, a gel was produced within 10
minutes after the incubation.
EXAMPLE 2
Gel Formation and Break-Up Using Temperature Change
[0071] 2.5 mL of a 0.1 M sulfuric acid solution was added to 100 mg
of cucurbit[7]uril and the resultant mixture was heated so that the
cucurbit[7]uril was completely dissolved in the sulfuric acid
solution. The resultant sol-phase composition was placed in a UV
cell, and the absorbance or transmittance of the composition with
respect to a temperature was measured to investigate a gelation
process.
[0072] In detail, the sol-phase composition was heated to
50.degree. C. and an absorbance (800 nm) with respect to a
temperature was then measured while gradually cooling down. The
results are shown as a photographic image and a graph in FIG. 5.
The graph of FIG. 5 shows a rapid absorbance increase
(transmittance decrease) at 37.degree. C. Such an absorbance change
reveals that gelation has occurred.
[0073] In FIG. 5, the phases of (a) and (b) of the graph
respectively correspond to those of (a) and (b) of the photographic
image.
EXAMPLE 3
Preparation of Pharmacologically Active Substance-Containing
Gel
[0074] 0.2 mL of a 1 M sulfuric acid solution was added to 10 mg of
cucurbit[7]uril and the resultant mixture was heated so that the
cucurbit[7]uril was completely dissolved in the sulfuric acid
solution. The resultant solution was incubated to reach a room
temperature to produce a gel. The gel was heated to obtain a sol.
0.2 eq. of oxaliplatin as a pharmacologically active substance was
completely dissolved in the sol, and the resultant mixture was then
incubated to reach a room temperature to produce an
oxaliplatin-containing gel. FIG. 6 is an image of the
oxaliplatin-containing gel.
EXAMPLE 4
Preparation of Light-Responsive Molecule-Containing Gel
[0075] 0.2 mL of a 1 M sulfuric acid solution was added to 10 mg of
cucurbit[7]uril and the resultant mixture was heated so that the
cucurbit[7]uril was completely dissolved in the sulfuric acid
solution. The resultant solution was incubated to reach a room
temperature to produce a gel. The gel was heated to obtain a sol.
0.1 eq. of trans-diaminostilbene undergoing a cis-trans transition
in response to light was completely dissolved in the sol to produce
a trans-diaminostilbene-containing gel undergoing a sol-gel
transition in response to light.
[0076] The trans-diaminostilbene-containing gel was exposed to 350
nm UV light for one hour to obtain a sol (see FIG. 7). Such a
gel-to-sol transition can be explained by the presumption that
trans-diaminostilbene is converted to cis-diaminostilbene in the
presence of UV light, and the cis-diaminostilbene hinders an
intermolecular interaction playing an important role in
gelation.
[0077] FIG. 7 shows that a color change has occurred upon
gel-to-sol transition in the presence of 350 nm UV light. This can
be explained by conversion of trans-diaminostilbene to
cis-diaminostilbene in the presence of UV light.
[0078] Meanwhile, the cis-diaminostilbene-containing sol was
converted to a gel in the presence of heat or long-wavelength (400
nm or more) light.
EXAMPLE 5
Preparation of Electrochemical Stimulus-Responsive Gel
[0079] 0.2 mL of a 0.5 M sulfuric acid solution was added to 10 mg
of cucurbit[7]uril and the resultant mixture was heated so that the
cucurbit[7]uril was completely dissolved in the sulfuric acid
solution. The resultant solution was incubated to reach a room
temperature to produce a gel. The gel was heated to obtain a sol.
0.7 eq. of benzoquinone undergoing an electrochemical redox
reaction was completely dissolved in the sol, and the resultant
mixture was then incubated to reach a room temperature to produce
an electrochemical stimulus-responsive gel.
[0080] Cyclic voltammetry for the gel was performed using a
Saturated Calomel Electrode (SCE) as a reference electrode, and the
cyclic voltammogram is shown in FIG. 8.
[0081] When a voltage of -0.1 V was applied to a sol obtained by
heating the gel, sol-to-gel transition occurred. This can be
explained as follows. That is, benzoquinone hindering gelation is
converted to hydroquinone under an electrochemical stimulus, and
thus, an intermolecular interaction playing an important role in
gelation is increased or hardly hindered.
[0082] In FIG. 9, (b) is an image of a sol obtained by dissolving
benzoquinone in a cucurbit[7]uril-containing solution and (a) is an
image of a gel obtained through conversion of benzoquinone to
hydroquinone when a voltage is applied to the sol of (b).
[0083] As described above, according to the present invention, a
cucurbituril-containing gel can be prepared by various methods. A
gel according to the present invention can include various
compounds. According to the characteristics of a compound contained
in a gel, a drug-containing gel or a gel capable of undergoing a
sol-gel transition in response to an external stimulus can be
prepared.
[0084] While the present invention has been particularly shown and
described with reference to exemplary embodiments thereof, it will
be understood by those of ordinary skill in the art that various
changes in form and details may be made therein without departing
from the spirit and scope of the present invention as defined by
the following claims.
* * * * *